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  • The electrophysiological mechanisms underlying high frequenc


    The electrophysiological mechanisms underlying high frequency activity observed in the PLA during SRAF could be reentry (rotor) or focal discharges (triggered activity). To discriminate between these mechanisms, we perfused ryanodine (10–40μM) or caffeine (5mM) to abolish calcium overload-mediated triggered activity during SRAF [46]. These pharmacological interventions successfully terminated a majority of SRAF (in 10/13 animals), whereas SRAF persisted despite drug application in the remaining cases (in 3/13 animals). These results suggest that SRAF in normal sheep hearts may be predominantly maintained by spontaneous focal discharges, although it should be noted that reentrant activity could also play a significant role in some cases.
    Stretch-related AF in the presence of adreno-cholinergic stimulation Similar to atrial stretch, autonomic input to the Ro 31-8220 methanesulfonate is important in AF initiation and maintenance, [48–50] but until recently the exact mechanisms whereby AF is maintained in the continuous presence of adreno-cholinergic stimulation remained unexplored. Recently, it has been shown that AF could be terminated by application of radiofrequency current catheter ablation to atrial areas containing cardiac ganglionated plexi, which function as modulators of autonomic input to the heart [51]. In addition to increasing trans-sarcolemmal calcium influx through the L-type calcium channel (ICa,L), adrenergic stimulation gives rise to intracellular calcium overload. On the other hand, cholinergic stimulation of muscarinic receptors opens the acetylcholine-activated potassium channel (IK,ACh), resulting in abbreviation of the atrial action potential duration. Recent studies suggest that simultaneous activation of adrenergic and cholinergic nerves (adreno-cholinergic stimulation, ACS) causes delayed afterdepolarizations (DADs) [50] and late phase-3 early afterdepolarizations (EADs) [48,52] through the activation of the forward mode of the sodium/calcium exchanger, thus resulting in focal discharges being expected to promote AF initiation and maintenance. We investigated the consequences of autonomic modification of SRAF in isolated sheep hearts by perfusing acetylcholine (1μM) and isoproterenol (0.03μM) simultaneously. Fig. 4A and B show a representative example of the activation pattern in the LAFW (phase map snap shots) during 2 SRAF episodes induced in the setting of ACS. In Fig. 4A, breakthrough resulted in wavebreak and rotor formation. In this case, the breakthrough (appearing at 4159ms) that emerged on the upper LA appendage underwent wavebreak, thus leading to the formation of a counterclockwise rotor with a cycle length of 72ms equaling 1/DFmax. On the other hand, while several rotors could be observed during a given AF episode, most were forced to drift and eventually terminate after 3 to 4 rotations by their interaction with the repetitively emerging breakthroughs. In Fig. 4B, the breakthrough that appeared near the center of the field of view at 956ms forced a rotor to drift over a long distance toward the LA roof. Then, collision of this rotor with a second rotor led to its annihilation. These results suggest that SRAF mechanisms in the presence of ACS resulted from a constant interaction between rotors and spontaneous focal discharges. We measured the substantial drifting distance that rotors underwent during SRAF in the setting of ACS. We traced the trajectory of phase singularities (PSs) at the rotor tip and quantified the spatio-temporal relationship between PSs and the breakthrough site as follows: first, the PS-to-center of breakthrough distance at the onset of the breakthrough was noted as distance (a; i.e., from the asterisk to the white circle in the upper panel in Fig. 4C). Distance (a) was then plotted against the PS-to-center value of the breakthrough distance after the rotor had undergone a half rotation; the latter was noted as distance (b) and measured between the white circles in the top and bottom panels. As plotted on the right graph (n=4), there was a nonlinear inverse relationship between rotor drifting and PS-breakthrough distance. Breakthroughs caused the most drifting when they occurred in the immediate vicinity of the PS, and the drifting Ro 31-8220 methanesulfonate effect tended to fade as the PS-breakthrough distance increased above 0.6cm. Interestingly, when spontaneous focal discharges were abolished, the rotors were long lasting and no longer drifted.